Differently from acute pain, which plays an important physiological action alerting the organism towards an incoming danger or damage, chronic pain does not play any protective action.
Chronic pain may be divided in two main categories: chronic inflammatory pain and neuropathic pain. The latter is due to a direct lesion on the nervous pathways by the noxa, which can be infectious, metabolic, vascular or other. In chronic inflammatory pain the lesioned tissues release algogenic factors which in turn damage nervous terminals creating a vicious mechanism which maintains and potentiates the perception of pain.
Chronic pain, of both neuropathic and inflammatory origin, is an important epidemiologic aspect of a high unmet medical need condition, i.e. of a therapeutic area which at present needs remarkable improvements since poorly effective treatments and a plethora of important noxious side-effects are present.
An increasing number of patients suffers from iatrogenic neuropathic pain, induced by anti-tumor therapies used in modern oncology. In particular, taxol derived drugs, cisplatin and vincristine are among the drugs which more often induce the insurgence of painful neuropathies. Currently no effective and/or well tolerated treatments exist for this kind of pain. In fact classical potent analgesic drugs such as lamotrigine (Renno S. I. 2006 J. Clin. Oncol. ASCO Annual Meeting Proceeding Part I vol. 24, No 18S:8530), gabapentin (Wong G. Y. 2005 J. Clin. Oncol. ASCO Annual Meeting Proceeding Part I vol. 23, No 16S:8001) or nortriptyline (Hammack J. E. 2002, Pain 98:195-203) are absolutely not satisfactory on the basis of their therapeutic index.
Nucleoside analog reverse transcriptase inhibitors (ddC, d4T, AZT) are commonly used as antiviral drugs in the treatment of AIDS. These drugs often cause the insurgence of peripheral neuropathies with different degrees of severity after prolonged treatment. As in the case of chemotherapeutic agents, these symptoms may be so strong to induce shortening or suspension of these life-saving therapies. The patterns of these neuropathies are clearly different from those induced by the progression of AIDS; they are in fact characterized by the sudden onset of very intense burning discomfort in both hands and feet at about the tenth week of treatment. HIV-induced neuropathies, on the contrary, have a very slow progression (Dubinsky R. M. 1989, Muscle Nerve 12:856-860). As for chemotherapy-induced neuropathies, it is difficult to treat this kind of pain.
The tricycic antidepressant amitryptiline and the sodium channel blocker mexiletine, effective on various forms of painful peripheral neuropathies, did not show any significant effect on this kind of neuropathic pain (Kieburtz K. 1998 Neurology 51:1682-1688). “Gabapentin showed some efficacy in relieving HIV-associated sensory neuropathies Hanh K. 2004 J Neurol 251: 1260-1266.).
Other forms of neuropathic pain may be caused by viral infections. Postherpetic neuralgia, for instance, is caused by the reactivation, long after the infection, of the varicella-zoster virus. This kind of neuropathy is characterized by the development of strong mechanical allodynia, frequent loss of sensitivity towards thermal stimuli and spontaneous intermittent pain. The severity of pain may compromise the quality of life of patients suffering from this condition.
Cephalea is a kind of chronic pain of high epidemiologic relevance. When cephalea occurs in a paroxystic way, with recurrent episodes lasting from hours to days and is associated to general sickness, it is called hemicrania.
The current treatment for hemicrania entails the use of different kind of analgesic agents, from non-steroidal anti-inflammatory drugs (NSAIDs) to opioids, antihistaminic drugs and ergotamine derivatives. In the last decade triptan 5HT2 antagonists have been used; they are often able to block an attack at its insurgence, if promptly administered. All these methods show serious limits in terms of both efficacy and toxicity. In the most severe cases, in which painful attacks recur many times a week, a pre-emptive therapy with antiepileptic, beta blocker and antidepressant drugs is performed. The maximum result which can be achieved with these pre-emptive therapies is 50% reduction in the frequency and intensity of the painful attacks, but not their definitive remission.
Inflammatory pain is another form of chronic pain. It is caused by the release of mediators which either directly activate the nociceptors localized on primary afferents or lower their activation threshold, thus increasing their sensitivity to either painful or non-painful stimuli of different nature. Excited primary afferents may in turn release neurotransmitters which can stimulate immune cells recruited by the inflammatory process causing the release of additional inflammatory mediators.
This phenomenon, defined ‘neurogenic inflammation’, leads to an autoamplification of the symptomotology of the patient. Osteoarthritis is a particularly severe and painful form of this kind of pathology. Osteoarthritis is a form of degenerative arthritis causing the breakdown and eventual loss of the cartilage of one or more joints. The most common symptom related to this pathology is pain in the affected joint, which increases in proportion to the amount of use of the joint. As the disease progresses there is pain at rest and later nocturnal pain. Even if a certain correlation between pain and the extension of the damage at the joint has been demonstrated, the precise etiology of this kind of pain is still obscure; in fact, patients with relatively small damages at the joints suffer from very intense pain and viceversa; this finding suggests that it is not a merely inflammatory pain, but that a neuropathic component is present as well. Recommended treatments include NSAIDs, steroids and opioids, but the use of these drugs is associated with the insurgence of severe side-effects; in addition, their efficacy is not complete in many instances (2000 Arthritis Rheum. 43:1905-1915).